Involvement of Striatal Cholinergic Interneurons and M1 and M4 Muscarinic Receptors in Motor Symptoms of Parkinson's Disease

Abstract

Over the last decade, striatal cholinergic interneurons (ChIs) have reemerged as key actors in the pathophysiology of basal-gangliarelated movement disorders. However, the mechanisms involved are still unclear. In this study, we address the role of ChI activity in the expression of parkinsonian-like motor deficits in a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion model using optogenetic and pharmacological approaches. Dorsal striatal photoinhibition of ChIs in lesioned ChAT cre/cre mice expressing halorhodopsin in ChIs reduces akinesia, bradykinesia, and sensorimotor neglect. Muscarinic acetylcholine receptor (mAChR) blockade by scopolamine produces similar anti-parkinsonian effects. To decipher which of the mAChR subtypes provides these beneficial effects, systemic and intrastriatal administration of the selective M1 and M4 mAChR antagonists telenzepine and tropicamide, respectively, were tested in the same model of Parkinson's disease. The two compounds alleviate 6-OHDA lesion-induced motor deficits. Telenzepine produces its beneficial effects by blocking postsynaptic M1 mAChRs expressed on medium spiny neurons (MSNs) at the origin of the indirect striatopallidal and direct striatonigral pathways. The anti-parkinsonian effects of tropicamide were almost completely abolished in mutant lesioned mice that lack M4 mAChRs specifically in dopamine D1-receptor-expressing neurons, suggesting that postsynaptic M4 mAChRs expressed on direct MSNs mediate the antiakinetic action of tropicamide. The present results show that altered cholinergic transmission via M1 and M4 mAChRs of the dorsal striatum plays a pivotal role in the occurrence of motor symptoms in Parkinson's disease.

Intrastriatal administration of botulinum neurotoxin A normalizes striatal D2R binding and reduces striatal D1R binding in male hemiparkinsonian rats

“…Preclinical studies on rodents illustrate that unbalanced limb use and turning behavior are reduced when abating the predominance of ACh by nigrostriatal intervention (Maurice et al, ; Won et al, ). Blockade of M 4 mAChR, located on D 1 MSNs (Lim et al, ), alleviates the akinetic dysfunction in a 6‐OHDA lesion model (Ztaou et al, ). ACh‐induced changes in electrophysiology of D 2 MSNs (Day, Wokosin, Plotkin, Tian, & Surmeier, ) provoke PD‐like akinesia in mice (Kondabolu et al, ; Maurice et al, ).…”

Roles of the M4 acetylcholine receptor in the basal ganglia and the treatment of movement disorders

“…The use of antimuscarinic agents, namely trihexyphenidyl, has a long‐established efficacy in reducing specific motor symptoms of PD and dystonia . In addition, trihexyphenidyl, and other poorly selective or nonselective antimuscarinic compounds, are effective at reducing abnormal movements in animal models of dystonia and PD with overt motor deficits . The efficacy of antimuscarinic compounds both preclinically and clinically suggest that mAChRs are important regulators of certain symptom domains of movement disorders.…”

“…Antimuscarinic compounds largely display only modest selectivity in vitro in pharmacological assays and, especially at doses needed to achieve efficacy, make it difficult to attribute the efficacy of the compound to a single mAChR . However, recent pharmacological advances as well as the use of genetic tools in combination with nonselective mAChR antagonists, such as the studies we have outlined previously, have raised the possibility that a single mAChR subtype may be responsible for the majority of efficacy seen clinically with current antimuscarinic compounds …”

Cholinergic modulation of striatal microcircuits

“…Impairment of striatal ChIs is central in the production of movement disorders (Pisani et al., ); altered cholinergic signaling is seen in a diverse class of syndromes that include Parkinson's disease (PD; Brichta et al., ; Kalia et al., ; Ztaou et al., ), dystonia (Peterson et al., ; Eskow Jaunarajs et al., ; Scarduzio et al., ), Tourette's syndrome (Xu et al., ; Albin et al., ), and Huntington's disease (Di Filippo et al., ).…”